Alzheimer's disease (AD) is a type of dementia that affects more than 15 million people of the entire world, and is predicted to affect more in the future, as the average lifetime increases. On the other hand, Down syndrome is a hereditary disease which occurs because of chromosome 21 trisomy (3 copies), and it is known that as Down syndrome patients grow, various AD-like changes in the brain gradually show up, and many Down syndrome patients in their middle ages are affected by AD. Preventing dementia is an important challenge in the aging society, and an effective preventive is strongly desired.
Statins, which are HMG-CoA (3-hydroxy-3-methylglutarylcoenzyme A) reductase inhibitor cholesterol-lowering agents, have been shown by epidemiological studies to have the effect of greatly lowering the occurrence rate of Alzheimer's disease, and expectations for dementia prevention by statins are rising. However, the action mechanism of LDL cholesterol decrease and AD are still unknown, rather a target molecule other than HMG-CoA reductase is speculated to be involved in the decline of AD occurrence rate, and it is necessary to clarify the dementia-related target molecule(s) of statins in order to carry out logical drug discovery for dementia prevention.
In recent years, on the other, the genome sequences of a variety of organisms have been elucidated and analyzed at the global level. For the human genome, in particular, a worldwide cooperative research project was implemented, and completion of analysis of all sequences thereof was announced in April 2003. As a result, it is becoming possible to analyze complex biological phenomena in the context of the functions and control of all genes, or networks of gene-gene, protein-protein, cell-cell, and individual-individual interactions. The genome information thus obtained has been significantly revolutionizing a number of industries, including drug development, as well as in academic sectors.
For example, it has been reported that there are about 480 kinds of target proteins for drugs having been in common use to date, and that these target proteins are limited to membrane receptors, enzymes, ion channels, or nuclear receptors and the like (J. Drews, Science, 287, 1960-1964, 2000). Meanwhile, target protein search based on genome information has discovered an extremely large number of target proteins, including novel proteins not covered in the conventional range of target proteins one after another, which are estimated to total about 1,500 kinds (A. L. Hopkins & C. R. Groom, Nature Reviews; Drug Discovery, 1, 727-730, 2002).
However, despite the fact that the research and development expenditures spent by pharmaceutical companies are increasing due to rises in infrastructuring costs for coping with vast amounts of data like genome information and clinical developmental costs, the number of new drugs approved per year is tending to decrease on the contrary (Nature Reviews; Drug Discovery, February, 2003). This shows that the above-described genome information is actually not efficiently utilized.
As a means for overcoming these circumstances, Nagashima et al. invented “Method, System, Apparatus, and Device for Discovering and Preparing Chemical for Medical and Other Uses” and filed a patent application for that invention (Japanese Patent Kohyo Publication No. 2004-509406).
Disclosed in that patent application are methods, systems, databases, user interfaces, software, media, and services that are useful for the evaluation of compound-protein interactions, and are also useful for the utilization of the information resulting from such an evaluation intended to discover compounds in medical and other areas. Furthermore, it is intended to produce a very large pool of novel target proteins for drug discovery, novel methods for designing novel drugs, and a pool of small substances for therapeutic purposes that are virtually synthesized as having been inconceivable in the past.
Specifically, disclosed in that patent application were a method of identifying a protein or partial protein that is appropriate as a novel drug discovery target, which comprises the following steps:    (i) a step for selecting a plurality of proteins or partial proteins showing desired affinity and specificity for a selected target compound;    (ii) a step for identifying the structure and function of the protein or the partial protein; and    (iii) a step for selecting a single protein or single partial protein having a desired function, and a method of discovering a drug, which comprises the following steps:    (i) a step for investigating the chemical structure of the target compound selected using the above-described method; and    (ii) a step for chemically modifying the structure of the selected target compound to optimize the affinity and specificity of the modified compound for the protein or the partial protein, which is appropriate as a novel drug target.
Furthermore, another feature of the method disclosed in that patent application resides in that the selected target compound is a compound approved for medical use.
Conventional drugs that have been used to date include many drugs for which target proteins are unknown, or for which target proteins are known but not all of whose pharmacological effects and adverse effects can be explained by mechanisms mediated by the proteins.
Typically, aspirin, one of the drugs that have longest been used, may be mentioned. When aspirin was launched in the market for the first time more than 100 years ago, the mechanism for its anti-inflammatory action was unclear. About 70 years later, aspirin was found to have cyclooxygenase (COX) inhibitory action. Still 20 years later, it was demonstrated that COX occurred in two subtypes: COX-1 and COX-2, that the primary pharmacological effect of aspirin was based on COX-2 inhibition, and that COX-1 inhibitory action was the cause of adverse effects such as gastrointestinal disorders. However, not all the target proteins for aspirin have been elucidated. In recent years, aspirin has been shown to exhibit anticancer action and antidementic action in clinical settings, but these pharmacological effects cannot be explained by COX inhibition. On the other, recent years have seen many papers reporting that aspirin acts on transcription factors such as IKKβ and on nuclear receptors such as PPAR-γ, but the relationship between these and the various pharmacological effects of aspirin remains unclear.
For these reasons, elucidating target proteins for traditionally used drugs can be said to be a very effective approach to discovering novel drug discovery target proteins.
Hirayama, one of the inventors of the above-described published patent, and others generated a database integrating the structural and physical property data on about 1,500 kinds of drugs commercially available in Japan, and found that existing pharmaceutical compounds share structural features (Chem-Bio Informatics Journal, 1, 18-22, 2001). Drugs that have been commonly used to date can be described as excellent in that they have cleared the issues of localization in the body and safety in their developmental processes. Searching novel target proteins with these existing drugs as probes, and selecting novel new drug candidate compounds on the basis of their structures is thought to be a highly reasonable and efficient approach.
A second problem arises concerning how to make use of the genome information during the search for novel target proteins. Solely determining the genome sequence is not sufficient to ensure the elucidation of the functions of all genes and the discovery of drug discovery target proteins. It is estimated that in humans, about 30,000 to 40,000 kinds of genes are present; taking into consideration variants from alternative splicing, there are reportedly more than 100,000 kinds of mRNA. It is important, therefore, that out of the vast amount of new genes revealed from the genome sequence, those having useful functions in industrial applications, including drug development, should be efficiently selected and identified.
In many cases of the genome sequences of eukaryotic organisms, each gene is divided into a plurality of exons by introns; therefore, it is impossible to accurately predict the structure of the protein encoded by the gene solely from the sequence information on the gene. In contrast, for a cDNA prepared from intron-excluded mRNA, information on the amino acid sequence of protein is obtained as information on a single continuous sequence, enabling easy determination of the primary structure thereof.
In particular, analyzing a full-length cDNA enables the identification of the mRNA transcription initiation point on the genome sequence based on the 5′-terminal sequence of the cDNA, and also enables analysis of factors involved in the stability of mRNA contained in the sequence and the expression control in the translation stage. Also, because the ATG codon, which serves as the translation initiation point, is present on the 5′ side, translation into protein in the right frame can be achieved. Therefore, by using an appropriate gene expression system, it is also possible to mass-produce the protein encoded by the cDNA, and to express the protein and analyze the biological activity thereof. Hence, it is considered that by performing an analysis using a protein expressed from full-length cDNA, important information that could not be obtained solely by genome sequence analysis is obtained, and that it is possible to discover novel target proteins that do not lie in the conventional category of drug discovery target proteins.
USP publication no. 20030159158 (Nef, Patrick, Aug. 21, 2003) discloses a screening method for an NCS1 agonist targeting NCS1, which is a kind of NCS. However, there is a plurality of molecular species of NCS, which is expressed specifically or complementarily in various tissues such as the cerebral nerve tissue, secretory tissue, immuno-related cells, epithelium of blood vessels, and relates to many functions. Hence, screening or designing directed to compounds with structures that are preferred for NCS binding is necessary in order to efficiently produce new pharmaceutical compounds that target the NCS family. The present invention discloses preferred structures for NCS binding, of which many in addition have structural motifs that exist in common drugs. For this reason, by taking the structure disclosed in the present invention as the starting point, it will be possible to efficiently screen or design a compound of high drug efficacy and safety. Furthermore, a screening method targeting NCS1 is disclosed in USP publication 20030159158. However, the NCS-binding compound and its screening method in the present application is directed to neurocalcin δ that belongs to the VILIPS family (Class B) and human hippocalcin-like protein 1 (or Visinin-like protein 3 or VILIP-3), which are indicated to be related to central nervous diseases, especially to dementia such as Alzheimer's disease, making it especially preferable for the development of therapeutic drugs for central nervous diseases centered around dementia. Note however, that the NCS-binding compound disclosed in the present invention is not limited to the VILIPS family (Class B), but comprises compounds that bind to the whole NCS family, including NCS 1.